Mumps virus is a common human pathogen that frequently invades the central nervous system (CNS). Strains of mumps virus differ in their cytopathogenicity (the degree of cytopathology that they cause in vitro) and their neurovirulence (the ability to invade the CNS and infect neurons) and there appears to be a correlation between the in vitro and in vivo biological effects. The molecular basis for these strain-dependent differences is not known and is the focus of the proposed experiments. Preliminary evidence suggests that the strain-dependent differences in cytopathogenicity and neurovirulence result, at least in part, from variation in the structure of the viral HN glycoprotein which mediates virion binding to host cells. The proposed experiments are designed to characterize the structure of the HN glycoprotein and to identify the functional domains that contribute to mumps virus cytopathogenicity and neurovirulence. Specifically, three different selection protocols will be used to isolate mumps virus variants that differ from the parental mumps virus strain by only minor alterations in the structure of the HN glycoprotein. The structural alterations will be defined at the level of the glycoprotein's amino acid sequence for those mumps virus variants that differ from the parental mumps virus strain in vitro and in vivo biological effects; in this way, the changes in primary structure that result in a modification in glycoprotein function and in virus virulence will be identified. Finally, an attempt will be made to generate polyclonal antibodies against putative functional domains of the HN glycoprotein by using as immunogens synthetic peptides with sequence homology to selected regions of the intact glycoprotein. Anti-peptide antibodies that recognize the HN glycoprotein in its native configuration will be tested for activity in in vitro functional assays and for a protective effect in the newborn hamster model of mumps meningoencephalitis. It is anticipated that the results of these studies will provide insight into the structure of the functional domains of the HN glycoprotein and will contribute to the understanding of the pathogenesis of mumps virus infection of the CNS.